Parkin Co-Regulated Gene (PACRG) is regulated by the ubiquitin-proteasomal system and is present in the pathological features of Parkinsonian diseases

Mutations in parkin are a common cause of early-onset autosomal recessive Parkinson's disease. Parkin Co-Regulated Gene (PACRG) is a novel gene that was discovered because of its close genetic proximity to parkin and the two genes were subsequently demonstrated to be regulated by a bi-directional promoter. However the role of PACRG has not been well characterized and the distribution of the protein in both normal and diseased brain is not known. Here, we report that like parkin, PACRG is regulated by the ubiquitin-proteasomal system. Immunohistochemistry identified PACRG in astrocytes throughout the brain and in pigmented noradrenergic neurons of the locus coeruleus. PACRG was also detected in Lewy bodies and glial cytoplasmic inclusions in patients with Parkinson's disease and Multiple System Atrophy, respectively. Together, these results demonstrate that PACRG is regulated by the ubiquitin-proteasomal system and may play a role in the pathogenesis of Parkinson's disease.     

Euglycemic hyperinsulinemia alters the response to orthostatic stress in older adults with type 2 diabetes

OBJECTIVE—Insulin has opposing influences on blood pressure by simultaneously increasing adrenergic activity and vasodilatating peripheral blood vessels. In this study, we sought to determine whether hyperinsulinemia affects tilt table responses in older adults with type 2 diabetes not complicated by orthostatic hypotension.RESEARCH DESIGN AND METHODS—Twenty-two older adults (mean age 71.7 ± 1.1) with diet-controlled or oral hypoglycemic drug–controlled type 2 diabetes were recruited. All subjects with orthostatic hypotension, diabetic nephropathy, and sensory neuropathy were excluded. Subjects underwent euglycemic-hyperinsulinemic clamp and placebo “sham clamp” sessions. Sequential euglycemic-hyperinsulinemic clamps were performed for 2 h at 40 mU · m⁻² · min⁻¹ (low dose) and 2 h at 80 mU · m⁻² · min⁻¹ (high dose), and each was followed by a head-up tilt table test at 70°C for 10 min.RESULTS—There were no incidents of presyncope during the sham clamp, whereas there were four presyncopal events during both the low-dose and high-dose tilts. Although the low-dose clamp showed no difference in the response between sessions (two-way ANOVA), subjects demonstrated a significantly larger decrease in mean arterial pressure (P = 0.005) and diastolic blood pressure (P = 0.08) during the high-dose tilt. Doppler measures of middle cerebral artery velocity were no different between the two sessions at either dose.CONCLUSIONS—The vasodilatory response to insulin can unmask orthostatic intolerance in older adults with type 2 diabetes, resulting in presyncopal symptoms. This could contribute to orthostatic hypotension in combination with other factors such as hyperthermia, hypovolemia, and adverse effects from medications.Orthostatic hypotension is common in older adults with (1) and without diabetes (2) and is usually attributed to autonomic neuropathy or age-related comorbidities (3). Insulin has profound cardiovascular properties, resulting in simultaneous adrenergic (4) and vasodilatory (5,6) responses that have opposing influences on blood pressure. Depending on the relative magnitude of sympathetic activation and vasodilation in older adults, insulin administration might be a contributing factor in orthostatic intolerance and syncope.Epidemiological studies have demonstrated that the use of insulin is a risk factor for syncope in older adults (7) and that insulin hypersensitivity is a predisposing factor for vasovagal syncope in young women (8). Previous work in young adults with type 1 diabetes has shown that insulin has no impact on standing blood pressure unless their diabetes is already complicated by autonomic neuropathy (9). However, the aging process itself is associated with a reduction in adrenergic sensitivity (10). Insensitivity to an insulin-mediated increase in adrenergic activity could allow the vasodilatory response to predominate and potentially uncover “latent” orthostatic hypotension in older adults with uncomplicated diabetes, similar to that demonstrated previously in young hyperthermic adults with diabetes (11).In the current study, we examined in older adults with type 2 diabetes (without baseline orthostatic hypotension) the impact of hyperinsulinemia (12) on arterial blood pressure and Doppler measures of cerebral blood flow during upright tilt. We hypothesized that in older adults with type 2 diabetes, the cardiovascular effects of insulin would precipitate orthostatic intolerance not present at baseline.     

Reflexology for symptom relief in patients with cancer

Complementary therapies are increasingly being used in hospices and hospitals alongside orthodox treatments in an attempt to improve patients' emotional, spiritual, psychological, and physical well-being. An average of 31% of UK patients with cancer use some form of complementary therapy. Many UK cancer centers, out-patient units, and hospices are providing complementary services. There is strong anecdotal evidence that complementary therapies assist in the palliation of physical and psychological symptoms. This systematic review examines the research evidence base for the effectiveness of reflexology in cancer care. The study reports the results of a systematic review following the Cochrane principles of systematic reviewing. No meta-analysis was possible. Studies were retrieved from a comprehensive search of electronic databases from their start dates. An initial search was carried out in 2003 and updated in 2005 to 2006. Eligible studies were randomized controlled trials, controlled before and after studies, and interrupted time-series studies. Participants were adults with a diagnosis of cancer, receiving care in any healthcare setting. Interventions were limited to reflexology carried out by a qualified therapist as distinguished from another healthcare professional carrying out a reflexology intervention. Outcome measures were patient-reported levels of physical and psychological indices of symptom distress and quality of life (measured using validated assessment tools).     

Temporal trends of mercury, cesium, potassium, selenium, and thallium in Arctic char (Salvelinus alpinus) from Lake Hazen, Nunavut, Canada: effects of trophic position, size, and age

Arctic char (Salvelinus alpinus L.), the top predator in High Arctic lakes, often is used as a bioindicator of Hg contamination in Arctic aquatic ecosystems. The present study investigated effects of trophic position, size, and age of Arctic char in Lake Hazen, the largest lake in the Canadian High Arctic (81 degrees 50'N, 70 degrees 25'W), on Hg bioaccumulation. In addition, several essential (Se, K) and nonessential elements (Tl, Cs) in char muscle tissue were examined to compare their behavior to that of Hg. Trophic position of Arctic char was identified by stable isotope (delta15N) signature. Temporal trends of Hg from seven sampling campaigns over a 16-year period (1990-2006) were investigated for the overall data and for one trophic class. Concentrations of Hg were not correlated with age but were positively related to fork length and trophic position. Large char with greater delta15N signatures (> 12 per thousand) had larger Hg concentrations (0.09-1.63 microg/g wet wt) than small char with smaller delta15N signatures (< 12 per thousand, 0.03-0.32 microg/g wet wt), indicating that Hg concentrations increased with trophic position. Nonessential Cs and Tl showed relationships to age, length, and trophic position similar to those of Hg, indicating their potential to bioaccumulate and biomagnify. Essential Se and K did not show these relationships. Concentrations of Hg were adjusted using delta15N, leading to less within-year variability and a more consistent temporal trend. The delta15N-adjusted trend showed no decline of Hg in Arctic char from Lake Hazen (1990-2006) in the overall data set and in the small morphotype. Trends for the same period before the adjustment were not significant for the overall data set, but a slight decrease was apparent in the small morphotype. The results confirm the need to consider trophic position and fish size when monitoring temporal trends of Hg, particularly for species with different morphotypes.     

Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors

Purpose MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. Methods Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. Results Five dose levels of MAC-321 ranging from 25 to 75 mg/m² were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m²). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m²; one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m² had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1–2 fatigue and grades 1–2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C _max value of less than 1 h. Mean C _max and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20–228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). Conclusions MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m². The major DLT was neutropenic fever. Four subjects had disease stabilization.     

The therapeutic potential of proteinase-activated receptors in arthritis

Proteinase-activated receptors are a family of seven-transmembrane G-protein-coupled receptors. Activation of PARs is initiated through cleavage of the N-terminus, unmasking a tethered ligand that can then interact with the receptor and lead to its activation. PARs exhibit both anti- and pro-inflammatory properties, although recent evidence has pointed towards a detrimental role for PARs, particularly PAR-2, in arthritis. Initial research using PAR-2 knockout mice identified PAR-2 as a key mediator of chronic joint inflammation. Further research examined the role of PAR-2 in human articular cell types, demonstrating upregulation of PAR-2 in cells from an inflammatory background compared with non-inflammatory cells, with PAR-2 levels being further upregulated by pro-inflammatory cytokines and growth factors. To date, there is no clinical evidence of a role for PAR-2 in vivo in humans, although recent studies utilizing human joint tissue and articular cells are emerging.     

The mandibular canal of the edentulous jaw.

The morphology of the mandibular canal after loss of teeth has received little detailed attention. Improved documentation of this topic would allow better interpretation of dental radiographs and would enable those engaged in tooth implantation to better understand the nature of the tissue into which the prostheses are placed. In this study on mandibles from seven dissecting room cadavers panoramic radiographs usually showed the mandibular canal clearly, an incisive canal less so. The wall of the mandibular canal was similar in dentate and edentulous mandibles, and was highly perforated, as suggested by Cryer (Anderson et al., 1991). In edentulous specimens, it was composed mainly of cancellous bone with only occasional single osteons. The inferior alveolar nerve near the mandibular foramen was a large trunk, consisting of three to four nerve bundles with connective tissue sheaths. It became more loosely arranged toward the mental foramen. Medial to the mental foramen, the nerves were frequently in the form of small bundles in the marrow. Any incisive canal was ill-defined and neurovascular bundles, when present, ran through a labyrinth of intertrabecular spaces.